Thermal and solvent effects on the NMR and UV parameters of some bioreductive drugs

• Published in: The Journal of chemical physics Vol. 123; no. 5; p. 054319
• Main Authors: Ramalho, Teodorico C, Taft, Carlton A
• Format: Journal Article
• Language: English
• Published: United States 01.08.2005
• Subjects: Antiprotozoal Agents - chemistry; Chemistry, Pharmaceutical - methods; Computer Simulation; Coumaric Acids - chemistry; Electrons; Hot Temperature; Magnetic Resonance Spectroscopy - methods; Metronidazole - chemistry; Models, Chemical; Models, Theoretical; Molecular Conformation; Solvents; Spectrophotometry, Ultraviolet; Ultraviolet Rays
• ISSN: 0021-9606; 1089-7690
• DOI: 10.1063/1.1996577

15N NMR chemical shifts and n-->pi* electronic transition energy for metronidazole (1) has been calculated and compared with experimental data. A detailed computational study of 1 is presented, with special attention to the performance of various theoretical methods for reproducing spectroscopic parameters in solution. The most sophisticated approach involves density functional based on the Car-Parrinello molecular dynamics simulations of 1 in aqueous solution (BP86 level) and averaging chemical shifts and deltaE(n-->pi*) over snapshots from the trajectory. In the NMR and UV calculations for these snapshots (performed at the B3LYP level), a small number of discrete water molecules are retained, and the remaining bulk solution effects are included via a polarizable continuum model (PCM). A good agreement with experiment is also obtained using static geometry optimization and NMR computation of pristine 1 employing a PCM approach. Further theoretical predictions are also reported for 17O NMR and deltaE(n-->pi*) of three hydroxycinnamic acid derivatives, which suggest that it is essential to incorporate the dynamics and solvent effects for NMR and UV calculations in the condensed phase.